Association of polymorphisms in C1orf106,IL1RN,and IL10 with post-induction infliximab trough level in Crohn’s disease patients

Background:Trough levels of the post-induction serum infliximab(IFX)are associated with short-term and long-term responses of Crohn’s disease patients to IFX,but the inter-individual differences are large.We aimed to elucidate whether single gene polymorphisms(SNPs)within FCGR3A,ATG16L1,C1orf106,OSM,OSMR,NF-jB1,IL1RN,and IL10 partially account for these differences and employed a multivariate regression model to predict patients’post-induction IFX levels.Methods:The retrospective study included 189 Crohn’s disease patients undergoing IFX therapy.Post-induction IFX levels were measured and 41 tag SNPs within eight genes were genotyped.Associations between SNPs and IFX levels were analysed.Then,a multivariate logistic-regression model was developed to predict whether the patients’IFX levels achieved the threshold of therapy(3 lg/mL).Results:Six SNPs(rs7587051,rs143063741,rs442905,rs59457695,rs3213448,and rs3021094)were significantly associated with the post-induction IFX trough level(P=0.015,P<0.001,P=0.046,P=0.022,P=0.011,P=0.013,respectively).A multivariate prediction model of the IFX level was established by baseline albumin(P=0.002),rs442905(P=0.025),rs59457695(P=0.049),rs3213448(P=0.056),and rs3021094(P=0.047).The area under the receiver operating characteristic curve(AUROC)of this prediction model in a representative training dataset was 0.758.This result was verified in a representative testing dataset,with an AUROC of 0.733.Conclusions:Polymorphisms in C1orf106,IL1RN,and IL10 play an important role in the variability of IFX post-induction levels,as indicated in this multivariate prediction model of IFX levels with fair performance.

Multi-alleles predict primary non-response to infliximab therapy in Crohn’s disease

Background:Infliximab(IFX)is the first-line treatment for patients with Crohn’s disease(CD)and is noted for its relatively high cost.The therapeutic efficacy of IFX has noticeable individual differences.Known single-gene polymorphisms(SNPs)are inadequate for predicting non-response to IFX.In this study,we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model.Methods:In this retrospective study,we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019.Primary non-response(PNR)and non-durable response(NDR)were evaluated using a simple endoscopic score for CD(SES-CD).A total of 125 SNPs within 44 genes were genotyped.A multivariate logistic-regression model was established to predict non-response to IFX.An area-under-the-receiver-operatingcharacteristics curve(AUROC)was applied to evaluate the predictive model performance.Results:Forty-two of 206(20.4%)patients experienced PNR and 15 of 159(9.4%)patients experienced NDR.Nine SNPs were associated with PNR(P<0.05).A PNR predictive model was established,incorporating 2-week high-sensitivity C-reactive protein(hs-CRP),rs61886887,rs61740234,rs357291,rs2269330,and rs111504845,and the AUROC on training and testing data sets were 0.818(P<0.001)and 0.888(P<0.001),respectively.At week 14,hs-CRP levels≥2.25 mg/L were significantly associated with NDR(AUROC=0.815,P<0.001).PNR-associated SNPs were not mutually associated with NDR,suggesting distinct mechanisms between PNR and NDR.Conclusion:Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.